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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >Striatal cholinergic cell ablation attenuates L-DOPA induced dyskinesia in parkinsonian mice
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Striatal cholinergic cell ablation attenuates L-DOPA induced dyskinesia in parkinsonian mice

机译：纹状体胆碱能细胞消融可减轻帕金森病小鼠的L-DOPA诱导的运动障碍

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摘要

3,4-Dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinesia (LID) is a debilitating side effect of long-term dopamine replacement therapy in Parkinson's Disease. At present, there are few therapeutic options for treatment of LID and mechanisms contributing to the development and maintenance of these drug-induced motor complications are not well understood. We have previously shown that pharmacological reduction of cholinergic tone attenuates the expression of LID in parkinsonian mice with established dyskinesia after chronic L-DOPA treatment. The present study was undertaken to provide anatomically specific evidence for the role of striatal cholinergic interneurons by ablating them before initiation of L-DOPA treatment and determining whether it decreases LID. We used a novel approach to ablate striatal cholinergic interneurons (ChIs) via Cre-dependent viral expression of the diphtheria toxin A subunit (DT-A) in hemiparkinsonian transgenic mice expressing Cre recombinase under control of the choline acetyltransferase promoter. We show that Cre recombinase-mediated DT-A ablation selectively eliminated ChIs when injected into striatum. The depletion of ChIs markedly attenuated LID without compromising the therapeutic efficacy of L-DOPA. These results provide evidence that ChIs play a key and selective role in LID and that strategies to reduce striatal cholinergic tone may represent a promising approach to decreasing L-DOPA-induced motor complications in Parkinson's disease.
机译：3,4-二羟基苯基-L-丙氨酸（L-DOPA）引起的运动障碍（LID）是帕金森氏病中长期多巴胺替代疗法的虚弱副作用。目前，很少有用于治疗LID的治疗选择，并且对导致这些药物诱导的运动并发症的发展和维持的机制尚不十分了解。我们以前已经表明，在慢性L-DOPA治疗后，药理学上胆碱能降低降低了帕金森氏病伴运动障碍的LID的表达。本研究旨在通过在开始L-DOPA治疗之前消融纹状胆碱能中间神经元并确定其是否降低LID来提供纹状胆碱能中间神经元的作用的解剖学特定证据。我们在胆碱乙酰转移酶启动子的控制下，通过表达Cre重组酶的半帕金森病转基因小鼠中白喉毒素A亚基（DT-A）的Cre依赖性病毒表达，使用了一种新的方法来消减纹状体胆碱能中间神经元（ChIs）。我们表明，Cre重组酶介导的DT-A消融注射入纹状体时选择性消除了ChIs。 ChIs的消耗可显着减弱LID，而不会损害L-DOPA的治疗功效。这些结果提供了证据，证明ChIs在LID中起关键和选择性的作用，并且降低纹状体胆碱能紧张度的策略可能是减少L-DOPA引起的帕金森氏病运动并发症的有前途的方法。

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